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OBJECTIVES: Chemoprevention can be a treatment for potentially malignant lesions (PMLs). We aimed to evaluate whether artemisinin (ART) and cisplatin (CSP) are associated with apoptosis and immunogenic cell death (ICD) in vitro, using oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC) cell lines, and whether these compounds prevent OL progression in vivo. METHODS: Normal keratinocytes (HaCat), Dysplastic oral cells (DOK), and oral squamous cell carcinoma (SCC-180) cell lines were treated with ART, CSP, and ART + CSP to analyze cytotoxicity, genotoxicity, cell migration, and increased expression of proteins related to apoptosis and ICD. Additionally, 41 mice were induced with OL using 4NQO, treated with ART and CSP, and their tongues were histologically analyzed. RESULTS: In vitro, CSP and CSP + ART showed dose-dependent cytotoxicity and reduced SCC-180 migration. No treatment was genotoxic, and none induced expression of proteins related to apoptosis and ICD; CSP considerably reduced High-mobility group box-1 (HMGB-1) protein expression in SCC-180. In vivo, there was a delay in OL progression with ART and CSP treatment; however, by the 16th week, only CSP prevented progression to OSCC. CONCLUSION: Expression of proteins related to ICD and apoptosis did not increase with treatments, and CSP was shown to reduce immunogenic pathways in SCC-180, while reducing cell migration. ART did not prevent the malignant progression of OL in vivo; CSP did despite significant adverse effects.

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BACKGROUND: The treatment of oral leukoplakia (OLK) with aminolaevulinic acid photodynamic therapy (ALA-PDT) is widespread. Nonetheless, there is variation in efficacy. Therefore, this study constructed a model for predicting the short-term efficacy and recurrence of OLK after ALA-PDT. METHODS: The short-term efficacy and recurrence of ALA-PDT were calculated by statistical analysis, and the relevant influencing factors were analyzed by Logistic regression and COX regression model. Finally, prediction models for total response (TR) rate, complete response (CR) rate and recurrence in OLK patients after ALA-PDT treatment were established. Features from pathology sections were extracted using deep learning autoencoder and combined with clinical variables to improve prediction performance of the model. RESULTS: The logistic regression analysis showed that the non-homogeneous (OR: 4.911, P: 0.023) OLK and lesions with moderate to severe epithelial dysplasia (OR: 4.288, P: 0.042) had better short-term efficacy. The area under receiver operating characteristic curve (AUC) of CR, TR and recurrence predict models after the ALA-PDT treatment of OLK patients is 0.872, 0.718, and 0.564, respectively. Feature extraction revealed an association between inflammatory cell infiltration in the lamina propria and recurrence after PDT. Combining clinical variables and deep learning improved the performance of recurrence model by more than 30 %. CONCLUSIONS: ALA-PDT has excellent short-term efficacy in the management of OLK but the recurrence rate was high. Prediction model based on clinicopathological characteristics has excellent predictive effect for short-term efficacy but limited effect for recurrence. The use of deep learning and pathology images greatly improves predictive value of the models.

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BACKGROUND: Oral leukoplakia (OLK), characterized by abnormal epithelial hyperplasia, is the most common precancerous oral mucosa lesion and is closely related to oxidative stress. Cucurbitacin B (CuB), a tetracyclic triterpenoid molecule derived from plants, has shown promising anti-proliferative and antioxidant effects in preclinical studies. However, whether CuB can play an antiproliferative role in OLK by regulating oxidative stress remains elusive. PURPOSE: To investigate the role of CuB in inhibiting the malignant progression of oral leukoplakia and to further explore its underlying mechanisms of action. METHODS: In vitro, the effect of CuB on the proliferation, migration, apoptosis, and cell cycle of OLK cells DOK was detected. The core genes and key pathways of OLK and CuB were analyzed in the transcriptome database, by using immunofluorescence, qRT-PCR, and Western blot to evaluate the expression levels of the ferroptosis markers ROS, GSH, MDA, Fe2+, and marker genes SLC7A11, GPX4, and FTH1. Immunohistochemistry of human tissue was performed to investigate the expression of the SLC7A11. In vivo, the model of OLK was established in C57BL/6 mice and the biosafety of CuB treatment for OLK was further evaluated. RESULTS: CuB substantially suppressed the proliferation of DOK cells. Bioinformatics analysis showed that the core targets of OLK crossing with CuB include SLC7A11 and that the essential pathways involve ROS and ferroptosis. In vitro experiments indicated that CuB might promote ferroptosis by down-regulating the expression of SLC7A11. We observed a gradual increase in SLC7A11 expression levels during the progression from normal oral mucosa to oral leukoplakia with varying degrees of epithelial dysplasia. In vivo experiments demonstrated that CuB inhibited the malignant progression of OLK by promoting ferroptosis in OLK mice and exhibited a certain level of biosafety. CONCLUSION: This study demonstrated for the first time that CuB could effectively inhibit the malignant progression of OLK by inducing ferroptosis via activating the SLC7A11/ mitochondrial oxidative stress pathway. These findings indicate that CuB could serve as the lead compound for the future development of anti-oral leukoplakia drugs.

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OBJECTIVE: To investigate the clinical efficacy of aminovalerate hydrochloride photodynamic therapy (PDT) for oral potentially malignant disorder (OPMD),oral leukoplakia (OLK), along with identifying the influencing factors.Additionally, the study aims to detect the rates of recurrence and malignancy after PDT. METHOD: 60 patients with OPMD who received PDT at our hospital from 2006 to 2021 were included in this study. Relevant patient medical data were collected and analyzed using SAS 9.4 software.The Mann-Whitney U test was used to retrospectively analyze the factors influencing clinical efficacy, as well as recurrence rate and malignant transformation rate (MTR) after treatment. RESULT: Among the 60 OPMD patients receiving PDT, complete remission in 13 (21.67 %), partial remission in 39 (65.00 %), and no remission in eight (13.33 %), resulting in an overall effective rate of 86.67 %.Fifteen patients experienced relapse, leading to a recurrence rate of 25.00 %. Among these relapses,11 patients occurred within one year after treatment, corresponding to an 18.33 % recurrence rate during that period. Moreover, nine patients developed malignant transformation (MT), resulting in an MTR of 15.00 %. Out of these patients, six individuals developed MT within one year after treatment, resulting in a one-year MTR of 10.00 %. CONCLUSION: The study findings indicate that PDT shows promising clinical efficacy in the treatment of OPMD, with relatively limited and tolerable postoperative adverse reactions. However, there remains a certain rate of recurrence and malignancy after treatment. Therefore, close attention should be paid to postoperative monitoring, regular follow-up, and further expansion of the sample size to observe its long-term efficacy.

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BACKGROUND: Topical photodynamic therapy (PDT) has demonstrated encouraging results in the treatment of oral leukoplakia (OLK). However, data on the clinical efficacy of PDT in Chinese patients with OLK are still limited. METHODS: Fifty patients diagnosed with OLK were enrolled, including patients with various dysplastic tissues. All patients received topical PDT with 5-aminolevulinic acid (5-ALA) as a photosensitizer. Clinical efficacy was evaluated 4 weeks after treatment. Follow-up was performed every 3 months during the first year and every 6 months during the second year. RESULTS: The overall response rate was 68% (34/50): 12% (n = 6) complete and 56% (n = 28) partial responses. Aneuploidy was reduced in the patients with dysplastic lesions. Oral pain and local ulcers developed in 52% of the patients (n = 26). Patients with a long history of OLK including hyperplasia and dysplastic lesions, as well as those with non-homogenous lesions, were more likely to develop pain and ulcer. During follow-up, the recurrence rate of hyperplasia and dysplastic lesions was 32% (n = 16) and the malignant transformation rate of dysplastic lesions was 4% (n = 2). Lesions on the buccal mucosa were associated with recurrence (P = 0.044; OR: 0.108, 95% CI: 0.013-0.915). CONCLUSION: Topical 5-ALA-mediated PDT is an effective treatment for OLK, particularly for homogenous leukoplakia, with few side effects. The buccal mucosa may be a protective factor that can reduce recurrence.

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Importance: Proliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape revealed a cytotoxic T-cell-rich microenvironment, providing strong rationale to investigate immune checkpoint therapy. Objective: To determine the safety and clinical activity of anti-programmed cell death 1 protein (PD-1) therapy to treat high-risk PVL. Design, Setting, and Participants: This nonrandomized, open-label, phase 2 clinical trial was conducted from January 2019 to December 2021 at a single academic medical center; median (range) follow-up was 21.1 (5.4-43.6) months. Participants were a population-based sample of patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia). Intervention: Patients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab (480 mg intravenously) every 28 days, followed by rebiopsy and intraoral photographs at each visit. Main Outcomes and Measures: The primary end point was the change in composite score (size and degree of dysplasia) from before to after treatment (major response [MR]: >80% decrease in score; partial response: 40%-80% decrease). Secondary analyses included immune-related adverse events, cancer-free survival (CFS), PD-1 ligand 1 (PD-L1) expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response. Results: A total of 33 patients were enrolled (median [range] age, 63 [32-80] years; 18 [55%] were female), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%) (95% CI, 20.4%-54.8%) had a response by composite score (3 MRs [9%]), 4 had progressive disease (>10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the trial, with a 2-year CFS of 73% (95% CI, 53%-86%). Two patients (6%) discontinued because of toxic effects; 7 (21%) experienced grade 3 to 4 immune-related adverse events. PD-L1 combined positive scores were not associated with response or CFS. Of 20 whole-exome sequenced patients, all 6 patients who had progression to OSCC after nivolumab treatment exhibited 9p21.3 somatic copy-number loss on pretreatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss. Conclusions and Relevance: This immune checkpoint therapy precancer nonrandomized clinical trial met its prespecified response end point, suggesting potential clinical activity for nivolumab in high-risk PVL. Findings identified immunogenomic associations to inform future trials in this precancerous disease with unmet medical need that has been difficult to study. Trial Registration: ClinicalTrials.gov Identifier: NCT03692325.

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AIM: The study aims to evaluate and compare the efficacy of Moringa oleifera leaf extract gel (2%) & Retino A cream (0.1%) in reducing the size of lesions in oral leukoplakia. OBJECTIVES: The present study aimed to evaluate the efficacy of two interventions, Moringa oleifera mucoadhesive gel and Retino-A cream, in reducing the size of lesions in patients with oral leukoplakia. Specifically, the objectives were: (1) to assess the efficacy of Moringa oleifera mucoadhesive gel in determining the reduction in lesion size, (2) to assess the efficacy of Retino-A cream in determining the reduction in lesion size, and (3) to compare the efficacy of Moringa oleifera mucoadhesive gel (2%) in determining the change in lesion size in oral leukoplakia patients. METHODS: Clinically diagnosed cases of oral Leukoplakia were included in this study. The sample size is 72. Thirty-six patients had lesion sizes ranging from 2- 4 cm, and 36 patients had lesion sizes ranging from 4.1 - 6 cm that were equally distributed in the case and control groups using the chit system. The case and control groups had 36 patients with an equal size range of lesions. The case and control group participants will be advised topical application of the intervention and Retino-A thrice daily using a sterile cotton bud. RESULTS: M. oleifera gel (2%) was found to be more effective in the reduction in the size of the lesion as compared to Retino-A in the treatment of oral leukoplakia patients. CONCLUSION: This study showed that M. oleifera mucoadhesive gel (2%) is an effective and safe treatment option for oral leukoplakia patients. It demonstrated a significant reduction in lesion size compared to Retino-A cream (0.1%) after 3 months of therapy, without any reported adverse effects. However, long-term follow-up studies are needed to evaluate its long-term effectiveness. The potent antioxidant property of M. oleifera makes it a promising candidate for further studies with concentration variations and in other potentially malignant oral disorders, such as lichen planus and OSMF. The development of chemotherapeutic drugs from M. oleifera for cancer treatment should also be considered. Overall, M. oleifera appears to be a promising natural alternative to synthetic drugs for the treatment of oral leukoplakia. KEY WORDS: Leukoplakia, Oral leukoplakia, premalignant lesion, precancer, potentially malignant disorders.

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OBJECTIVE: This study aims to evaluate the efficacy of photodynamic therapy (PDT) in the treatment of oral leukoplakia and explore the subgroup factors that may influence its effectiveness. METHODS: A systematic search was conducted in PubMed, Embase, the Cochrane Library, and Web of Science databases to identify relevant studies. Meta-analysis was performed using Stata15.0 software. Cochran's Q test and I2 statistics were used to evaluate heterogeneity, egger's test was used to evaluate publication bias. RESULTS: The analysis of 17 studies included in this study suggests that PDT may be effective in achieving complete response (CR) [ES = 0.50, 95%CI: (0.33,0.66)], partial response (PR) [ES = 0.42, 95%CI: (0.27,0.56)], no response (NR) [ES = 0.19, 95%CI: (0.11,0.27)]in patients with oral leukoplakia. The recurrence rate was also evaluated [ES = 0.13, 95%CI: (0.08,0.18)]. Subgroup analysis showed that various factors such as light source, wavelength, medium, duration of application, clinical and pathological diagnosis classification influenced efficacy of PDT. The lesion areas of the leukoplakia after treatment were reduced by 1.97cm2 compared with those before treatment. CONCLUSION: Our findings show that PDT is a viable treatment for oral leukoplakia. However, the effectiveness of the therapy may depend on several factors, as suggested by our subgroup analyses. (Registration no. CRD42023399848 in Prospero, 26/02/2023).

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Oral leukoplakia (OLK) is one of the most common potentially malignant disorders. High-risk lesions require early intervention before developing into oral cancer. Photodynamic therapy (PDT) is a noninvasive technique for premalignant lesions. Scalpel biopsy remains a reliable method for monitoring the prognosis of OLK, but it is an invasive procedure with poor reproducibility to suspicious lesions. DNA aneuploidy cytology by oral cytobrush has been proposed as a promising objective and noninvasive tool in screening and diagnosing premalignant and malignant lesions. Here, we discussed the significance of artificial intelligence (AI)-assisted DNA aneuploidy cytology by image cytometry (DNA-ICM) for surveilling non-homogeneous OLK with moderate-to-severe dysplasia that was treated by 5-aminolevulinic acid-mediated PDT (ALA-PDT). The present study provides a scheme of the sequential management and surveillance strategy for OLK.

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BACKGROUND: Oral leukoplakia and oral submucous fibrosis are potentially malignant disorders of the oral cavity, with high rates of recurrence and malignant transformation. Notably, the malignant transformation rate of oral leukoplakia with concomitant oral submucous fibrosis is significantly higher than that of oral submucous fibrosis or oral leukoplakia alone. However, the management of these conditions is not well defined. Photodynamic therapy is a minimally invasive treatment modality that effectively targets oral potentially malignant disorders, such as oral leukoplakia, erythroleucoplakia, and verrucous hyperplasia, with the advantages of being repeatable and leaving no scarring. CASE PRESENTATION: We report the case of a 42-year-old man with concomitant oral leukoplakia and oral submucous fibrosis almost involving the entire right buccal mucosa, who underwent six sessions of topical 5-aminolevulinic acid-mediated photodynamic therapy. RESULTS: Photodynamic therapy successfully eradicated whitish plaques and improved mouth opening without any adverse effects. Although photodynamic therapy failed to completely reverse the pathological changes, grading of epithelial dysplasia did not progress and clinical recurrence was not found during the 10-month follow-up. CONCLUSION: In conclusion, topical 5-aminolevulinic acid-mediated photodynamic therapy appears safe and has excellent clinical efficacy against oral leukoplakia-concomitant oral submucous fibrosis, but long-term follow-up is necessary.

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AIM: This study aimed to treat smoker's palate (SP) using 5-aminolevulinic acid (5-ALA)-mediated photodynamic therapy (PDT). METHODS: A total of 24 patients with SP were divided into two groups: group-I (test group; n = 12); and group-II (control group; n = 12). Group-I patients were treated with 5-ALA-mediated PDT, while group-II patients were advised to cease the smoking habit during the entire duration of the study and later. PDT was repeated on days 3, 7, and 14 (i.e., a total of four sittings including day 0 [baseline]). Later, the participants were called for follow-up after week-4 (1st follow-up), week-6 (2nd follow-up), and week-8 (3rd follow-up) after the completion of the treatment. The SPSS version 22.0 was used for data analysis. RESULTS: Group-I patients showed a statistically significant improvement when all three time points were assessed (p < 0.0001). Similarly, the same trend was observed in the group-II participants (p < 0.001), however, the difference between both groups (i.e., group-I [test group] and group-II [control group]) was larger. CONCLUSION: The findings of this clinical trial indicated a promising and satisfactory decrease in the clinical features of the smoker's palate without any adverse impacts utilizing 5-aminolevulinic acid-mediated photodynamic therapy. Hence, 5-ALA-mediated PDT appeared to be a promising treatment option together with smoking cessation.

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OBJECTIVE: The aim the study is to increase the effectiveness of the treatment of severe forms of leukoplakia with the use of photodynamic therapy. MATERIAL AND METHODS: 120 patients with severe forms of leukoplakia were examined. 30 patients were diagnosed with Cr and carcinoma in situ, and therefore they were excluded from the study. In 90 patients, the diagnosis was confirmed by histological and IHC studies. Before the use of photodynamic therapy, the degree of saturation of pathological foci with a photosensitizer was determined by the method of fluorescent diagnostics using the LED device «RFS-400¼. RESULTS: As a result of treatment with photodynamic therapy using a 2nd generation photosensitizer («Photoditazine¼ 0.5% gel penetrator), a significant improvement in the epithelization of lesion elements was observed: in 92% of patients with verrucous leukoplakia and in 83% of patients with erosive leukoplakia. CONCLUSION: The use of photodynamic therapy for the treatment of patients with complicated forms of leukoplakia is an effective method of treatment for this pathology.

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Objetivo: La leucoplasia oral es el desorden maligno de la mucosa bucal más prevalente a nivel global y su manejo clínico sigue siendo un desafío. Se llevó a cabo una revisión sistemática para determinar la eficacia clínica de la terapia fotodinámica mediada por ácido 5-aminolevulínico tópico como una alternativa de quimio-prevención para las diferen- tes formas clínicas de la leucoplasia oral. Materiales y métodos: Empleando términos MeSH, se realizó una búsqueda exhaustiva en diferentes bases digi- tales de ensayos clínicos publicados en inglés en los últimos 30 años acerca del uso de la terapia fotodinámica mediada por ácido 5-aminolevulínico tópico como fotosensibilizador, y radiación láser de baja intensidad o luz LED como posibles fuentes de iluminación. Resultados: La revisión sistematizada que aplicó la guía PRISMA mostró una eficacia del 88,6% para este modo de fototerapia en el manejo de leucoplasias orales, con un 60,7% de respuesta completa y 27,9% de respuesta parcial. Además, el tamaño de efecto fue mayor para las formas clíni- cas homogéneas con cambios displásicos, independientemen- te del tipo de fuente de luz. La ausencia de respuesta fue del 11,4%, pero la evidencia empleada en este análisis fue mo- derada. Conclusión: La terapia fotodinámica mediada por áci- do 5-aminolevulínico tópico parece ser una alternativa útil en el manejo onco-preventivo de lesiones de leucoplasia oral. Sin embargo, es recomendable ejecutar ensayos clínicos controla- dos y aleatorizados con metodologías homogéneas que per- mitan generar un meta-análisis con un alto nivel de evidencia

Aim: Oral leukoplakia is globally the most prevalent ma- lignant disorder of the oral mucosa and its clinical manage- ment remains a challenge. A systematic review was carried out to determine the clinical efficacy of photodynamic therapy mediated by topical 5-aminolevulinic acid as an alternative for chemoprevention in the different clinical forms of oral leu- koplakia. Materials and methods: Using MeSH terms, an ex- haustive search was carried out in different digital databases of clinical trials published in English in the last 30 years on the use of photodynamic therapy mediated by topical 5-ami- nolevulinic acid as a photosensitizer, and low-intensity laser radiation or LED light as possible lighting sources. Results: The systematized review using PRISMA guide- lines showed an efficacy of 88.6% for this mode of photother- apy in the management of oral leukoplakias, based on 60.7% of complete response and 27.9% of partial response. In addi- tion, the effect size was larger in homogeneous clinical forms with dysplastic changes, regardless of the type of light source. There was an 11.4% of absence of response, but the evidence used in this analysis was moderate. Conclusion: Photodynamic therapy mediated by topical 5-aminolevulinic acid seems to be a useful alternative in the onco-preventive management of oral leukoplakia lesions. However, it is recommendable to perform controlled and ran- domized clinical trials with homogeneous methodologies that allow the generation of a meta-analysis with a high level of evidence (AU)

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Proliferative verrucous leukoplakia (PVL) is a rapidly progressing, easily relapsed, and cancer-prone oral potential malignant disease (OPMD), for which treatment options are currently limited. Non-invasive photodynamic therapy (PDT) uses specific wavelengths of light to excite photosensitizers and generate reactive oxygen species to induce cytotoxic effects, and it is selective for malignant tissues. However, the lesions of PVL often show hyperkeratosis, which limits the penetration of photosensitizers into the tissue and affects the effectiveness of PDT. Laser, a safe and efficient treatment, has shown great advantages in aiding photosensitizer delivery, due to its ability to accelerate the penetration of 5-aminolevulinic acid (5-ALA) and improve the accumulation of protoporphyrin IX (PPIX) in tissues. In the case report, we achieved complete remission and no recurrence at 8 months in a patient with PVL through laser-assisted PDT, which obtained satisfactory clinical effect and well protected the appearance and function of oral cavity.

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Photodynamic therapy (PDT) is an alternative microinvasive approach with satisfying results in the treatment of oral leukoplakia (OL). PDT combined with laser irradiation shows promise, safety and efficacy in treating OL. The efficacy of waterlase (YSGG) combined with PDT was studied by brush and tissue biopsy. Seventy-one patients with histologically diagnosed OL were enrolled, including patients with mild to moderate dysplasia, severe dysplasia and various dysplastic tissues. Patients were evaluated at baseline (t0), the end of treatment (t1) and 1 year later (t2). At t1, PDT showed a significant therapeutic effect on OL with mild to moderate dysplasia. Clinical and histological examinations revealed 60 cases (84.51%) of complete remission and 11 cases (15.49%) of partial remission. On brush biopsy, all PDT-treated patients showed reduced aneuploidy and normal histological findings. Unfortunately, at t2, 9 patients relapsed with OL, which may be related to continued smoking and betel nut chewing. At t2, 5 patients developed new severe epithelial dysplasia and even carcinoma in situ in other areas, mostly the tongue. ALA-mediated PDT combined with YSGG is effective in treating OL, particularly that with mild to moderate dysplasia. However, severe dysplasia may present undesirable effects, and the mechanism remains to be further investigated. ALA-mediated PDT combined with YSGG provides a new method for OL treatment.

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Non-homogeneous oral verrucous/granular leukoplakia is a potentially malignant disorder with a higher malignant transformation rate than homogeneous leukoplakia. Surgical resection is commonly performed since the disease is often malignant and refractory. However, surgical intervention is painful and heavily impairs the patients' quality of life. Photodynamic therapy is minimally invasive, can be administered repeatedly, and is widely used to treat potentially malignant disorders and cancers. We report a case of oral verrucous/granular leukoplakia with extensive lesions in a 58-year-old man. Histopathological examination showed moderate-to-severe dysplasia and a tendency of malignant transformation in the focal area. At this stage, the patient was recommended for surgery by the oncology department. With the patient's consent, photodynamic therapy was performed at our department while he awaited the surgery. In the absence of any auxiliary measures, eight treatments with 5-aminolevulinic acid-mediated photodynamic therapy achieved favorable results, and there no recurrence was observed after 7 months of follow-up. This result suggests that photodynamic therapy should be considered when treating potentially malignant disorders such as oral verrucous/granular leukoplakia, or as pre-treatment before surgical resection.

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Some oral squamous cell carcinomas (OSCCs) originate from preexisting oral potentially malignant disorders (OPMDs). Oral leukoplakia (OLK) is the most common and typical OPMD in the clinic, so treatment for it is essential to reduce OSCC incidence. Local chemotherapy is an option other than surgery considering the superficial site of OLK. However, there are no standardized drugs applied to OLK, and traditionally used chemotherapeutic drugs revealed limited efficacy for lack of adhesion. Hence, there is a growing demand to prepare new agents that combine mucoadhesion with an anti-OLK effect. Here, an isoguanosine-tannic acid (isoG-TA) supramolecular hydrogel via dynamic borate esters was successfully fabricated based on isoG and TA. Previously reported guanosine-TA (G-TA) hydrogel was also explored for an anti-OLK effect. Both gels not only exhibited ideal adhesive properties but also integrated anti-OLK activities in one system. In vitro cell viability indicated that isoG and TA inhibited the proliferation of dysplastic oral keratinocytes (DOKs). The in vivo OLK model evidence revealed that both gels showed potential to prevent OLK canceration. In addition, the probable anti-DOK mechanisms of isoG and TA were investigated. The results indicated that isoG could bind to adenosine kinase (ADK) and then affected the mammalian target of rapamycin (mTOR) pathway to inhibit DOK proliferation. TA could significantly and continuously reduce reactive oxygen species (ROS) in DOKs through its antioxidant effect. ROS plays an important role in the progression of cell cycle. We proved that the low level of ROS may inhibit DOK proliferation by inducing G0/G1 arrest in the cell cycle. Altogether, this study innovatively fabricated an isoG-TA hydrogel with ideal adhesion, and both isoG and TA showed in vitro inhibition of DOKs. Moreover, both isoG-TA and G-TA hydrogels possessed potential in delaying the malignant transformation of OLK, and the G-TA hydrogel showed a better statistical effect, providing an effective strategy for controlling OLK.

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OBJECTIVES: This study aimed to review the results of oral leucoplakia (OL) using ablative fractional laser-assisted photodynamic therapy (AFL-PDT) and to further evaluate the risk factors for recurrence and malignant transformation. MATERIALS AND METHODS: Forty-eight patients diagnosed with OL using histopathology were enrolled in this study. All patients received one session of AFL-PDT. Therapeutic efficacy was evaluated 1 month posttreatment. Follow-up was scheduled every 3 months in the first year and every 6 months thereafter. RESULTS: An overall positive response rate of 87.5% (42/48) was achieved, including 62.5% (30/48) complete responses and 25.0% (12/48) partial responses. During the 3-year follow-up period, the recurrence and malignant transformation rates were 37.5% (18/48) and 8.3% (4/48), respectively. Lesions on gingiva/palate seemed to be associated with recurrence (p < 0.001; odds ratio [OR]: 1.64, 95% confidence interval [CI]: 1.13-2.37). The severity of epithelial dysplasia (p = 0.02; OR: 2.93, 95% CI: 1.96-4.42) and recurrence (p = 0.016; OR: 3.14, 95% CI: 2.04-4.84) were associated with a predisposition to malignant transformation. CONCLUSIONS: AFL-PDT is an effective management of OL, but requires close follow-up. OL lesions on the gingiva/palate are predisposed to recurrence. OLs that recur with moderate/severe epithelial dysplasia have a higher risk of transforming into oral squamous cell carcinoma.

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Oral leukoplakia (OLK) has gained extensive attention because of the potential risk for malignant transformation. Photosensitizers (PSs) played an indispensable role in the photodynamic therapy (PDT) of OLK, but the poor light sensitivity greatly hampered its clinical application. Herein, a novel organic photosensitive ITIC-Th nanoparticles (ITIC-Th NPs) were developed for OLK photodynamic/photothermal therapy (PTT). ITIC-Th NPs present both high photothermal conversion efficiency (~ 38%) and suitable reactive oxygen species (ROS) generation ability under 660 nm laser irradiation, making them possess excellent PDT and PTT capability. In 4-nitroquinoline 1-oxide (4NQO)-induced oral precancerous animal models, ITIC-Th NPs effectively suppress the OLK's cancerization without apparent topical or systemic toxicity in vivo. This study offers a promising therapeutic strategy for PDT and PTT in OLK treatment, and this study is the first interdisciplinary research in the field of multimodal therapy for OLK.

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